Selective serotonin receptor antagonists and therapeutic applications thereof

ABSTRACT

Spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine (SPAN) and derivatives thereof are provided as selective serotonin receptor antagonists. The compounds are selective, high affinity antagonists of 5-HT 2  serotonin receptors. The compounds are useful as antidepressant and antianxiety agents.

This application claims the benefit of U.S. provisional applications60/377,606 and 60/438,798, filed May 6, 2002 Jan. 9, 2003 respectively.

This invention was made using funds from grants from the NationalInstitutes of Health having grant number MH57969. The government mayhave certain rights in this invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention generally relates to selective serotonin receptorantagonists and methods of their use as antidepressant and antianxietyagents. In particular, the invention providesspiro[9,10-dihydroanthracene]-9,3′-pyrrolidine (SPAN) and derivativesthereof as selective high affinity antagonists of 5-HT receptors.

2. Background of the Invention

Serotonin (5-hydroxytryptamine, or 5-HT; see Formula 1) is a product oftryptophan metabolism that mediates many diverse physiologicalactivities. Most fundamentally, this well-characterized tryptaminederivative functions as a potent neurotransmitter by regulatingG-protein coupled and ligand gated ion channel receptors at the surfaceof nerve and muscle cells. This activity is mediated by the binding ofserotonin to several classes of cell-surface 5-HT receptors. Numerous5-HT receptors are known and have been categorized into several families(5-HT₁-5-HT₇) and some are further divided into subfamilies (e.g.5-HT_(2A) and 5-HT_(2C)). Many of the 5-HT receptors have been clonedand their specific functions elucidated.

Imbalances in serotonin activity are believed to be responsible for avariety of clinically recognized disorders. For example, many braindisorders in humans are associated with fluctuations in serotonin levelsand are effectively treated with drugs that interact specifically with5-HT receptors or that block the reuptake of serotonin into thepresynaptic axon terminals, suggesting that serotonin dysregulation maybe involved in these disorders. For example, serotonin receptor ligandsare clinically approved as drugs for the treatment of depression,psychosis, anxiety, and certain sexual aberrations, as well as for otherconditions such as migraine headaches, chemotherapy-induced nausea, highblood pressure, certain abnormal cardiovascular activities and abnormalthermoregulation.

However, most of these existing agents are relatively nonselective inthat they exhibit affinities for several 5-HT receptor classes, as wellas for central dopaminergic, noradrenergic, histaminergic, and/orcholinergic receptors, as well as blocking serotonin and dopaminereuptake into the nerve terminus. As a consequence of activity atnonserotonergic sites, the use of these agents may result in undesirableside effects such as tardive dyskinesia, tardive dystonia, excessiveweight gain, etc. These side effects can be debilitating and may requireclinical treatment in and of themselves. The possibility of theoccurrence of side effects is a cause of distress to patients, and is alikely contributor to patient non-compliance with suggested drug therapyregimens.

Ligands which bind with varying degrees or selectivity to some familiesof 5-HT receptors are known. For example, U.S. Pat. Nos. 5,496,957 and5,504,101 to Glennon (Mar. 5, 1996 and Apr. 2, 1996, respectively, thecomplete contents of which are hereby incorporated by reference)describe agents which bind to the 5-HT_(1Dβ) receptor. And U.S. Pat. No.5,942,536 to Fritz et al. (Aug. 24, 1999, the complete contents of whichis hereby incorporated by reference) describes agents which bind to the5-HT_(1f) receptor. Roth et al. (1994) describe the binding affinitiesof 36 typical and atypical antipsychotic agents to 5-HT₆ and 5-HT₇receptors, and Glennon et al. (1989) describe classes of agents whichbind to 5-HT_(1A) receptors. Finally, Glennon et al. (1994) describe theeffect of different amine substitutions on phenylalkylamine andindolylalkylamine derivatives which bind to 5-HT_(2A) and 5-HT_(2C)serotonin receptors. There is an ongoing need for the development ofalternative agents that selectively bind to specific families of 5-HTreceptors with high affinity.

SUMMARY OF THE INVENTION

It is an object of this invention to provide compounds having theformula

In the compounds, R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl,alkylaryl, or substituted or unsubstituted branched or unbranched C₁-C₁₀alkyl or alkylaryl, and may be the same or different, and X may be a)carbon with two —H substituents, b) carbon with one or two lower alkylsubstituents, or c) a heteroatom or heteroatomic group selected from thegroup consisting of —O—; —S—; or —SO₂—. In some embodiments, R1 may be—H, —CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂) ₄CH₃, phenyl, or —OH. In someembodiments, R2 may be —H, —CH₃ or CH₂Ph. In some embodiments, X may be—CH₂—, —C(CH₃)₂—, —O— or —S—.

Specific embodiments include compounds with the following formulas:

The invention further provides a pharmaceutical composition comprising,a compound of formula

in which R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl, alkylaryl, orsubstituted or unsubstituted branched or unbranched C₁-C₁₀ alkyl oralkylaryl, and may be the same or different, and X may be a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,or c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; or —SO₂—. In some embodiments, R1 may be —H,—CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂)₄CH₃, phenyl, or —OH. In some embodiments,R2 may be —H, —CH₃ or CH₂Ph. In some embodiments, X may be —CH₂—,—C(CH₃)₂—, —O— or —S—, and a pharmaceutically acceptable carrier.

The present invention also provides a method of treating a conditioncaused by abnormal serotonin activity in a patient in need thereof. Themethod includes the step of administering a compound of formula

in which R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl, alkylaryl, orsubstituted or unsubstituted branched or unbranched C₁-C₁₀ alkyl oralkylaryl, and may be the same or different, and X may be a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,or c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; or —SO₂—. In some embodiments, R1 may be —H,—CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂)₄CH₃, phenyl, or —OH. In some embodiments,R2 may be —H, —CH₃ or CH₂Ph. In some embodiments, X may be —CH₂—,—C(CH₃)₂—, —O— or —S—. The compound is administered in a quantitysufficient to ameliorate symptoms of said condition in said patient. Thecondition may be for example, clinical depression or anxiety,schizophrenia, schizoaffective disorder, and various eating and sleepingdisorders. The compound may be an antagonist of 5HT2 receptors, anantagonist of H1 receptors, or an antagonist of both 5HT2 receptors andH1 receptors.

The invention further provides a method of blocking a 5HT2 receptor in apatient in need thereof. The method includes the step of administeringto the patient of a compound of formula

in which R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl, alkylaryl, orsubstituted or unsubstituted branched or unbranched C₁-C₁₀ alkyl oralkylaryl, and may be the same or different, and X may be a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,or c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; or —SO₂—. In some embodiments, R1 may be —H,—CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂)₄CH₃, phenyl, or —OH. In some embodiments,R2 may be —H, —CH₃ or CH₂Ph. In some embodiments, X may be —CH₂—,—C(CH₃)₂—, —O— or —S—. The compound is administered in a quantitysufficient to block the 5HT2 receptor.

The invention further provides a method of blocking an H1 receptor in apatient in need thereof The method includes the step of administering tothe patient a compound of formula

in which R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl, alkylaryl, orsubstituted or unsubstituted branched or unbranched C₁-C₁₀ alkyl oralkylaryl, and may be the same or different, and X may be a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,or c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; or —SO₂—. In some embodiments, R1 may be —H,—CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂)₄CH₃, phenyl, or —OH. In some embodiments,R2 may be —H, —CH₃ or CH₂Ph. In some embodiments, X may be —CH₂—,—C(CH₃)₂—, —O— or —S—. The compound is administered in a quantitysufficient to block the H1 receptor.

The invention further provides a method of blocking both a 5HT2 receptorand an H1 receptor in a patient in need thereof. The method includes thestep of administering to the patient a compound of formula

in which R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl, alkylaryl, orsubstituted or unsubstituted branched or unbranched C₁-C₁₀ alkyl oralkylaryl, and may be the same or different, and X may be a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,or c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; or —SO₂—. In some embodiments, R1 may be —H,—CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂)₄CH₃, phenyl, or —OH. In some embodiments,R2 may be —H, —CH₃ or CH₂Ph. In some embodiments, X may be —CH₂—,—C(CH₃)₂—, —O— or —S—. The compound is administered in a quantitysufficient to block both the 5HT2 and the H1 receptor.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

The present invention provides certain compounds that exhibit highbinding affinity for serotonin receptors 5-HT_(2A) and 5-HT_(2C).Without being bound by theory, the compounds appear to act asantagonists of these receptors. By “antagonist” we mean the compoundsblock the action of endogenous serotonin at the receptor and preventactivation of the receptor.

Further, the compounds of the present invention are highly selective,being essentially devoid of affinity for the dopamine D2 receptors andthe serotonin and norepinephrine transporters. As such, the compoundsare useful for treating conditions for which it is desirable toselectively block serotonin receptor function with an antagonist.Because the compounds are highly selective for the target receptors,they cause fewer side effects than previously known serotonin receptorligands.

A generic chemical structure of the compounds of the present inventionis given in Formula 2.

In Formula 2:

R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl, alkylaryl, orsubstituted or unsubstituted branched or unbranched C₁-C₁₀ alkyl oralkylaryl, and may be the same or different. X may be a) carbon with two—H substituents, b) carbon with one or two lower alkyl substituents, orc) a heteroatom or heteroatomic group, examples of which include but arenot limited to —O—, —S—, and —SO₂—.

By “alkylaryl” we mean an aryl substituted with a C₁-C₄ alkyl, or aC₁-C₁₀ alkyl bridging between an aryl substituent (e.g. phenyl) and thephenyl moiety depicted in Formula 2. “Phenyl” and “benzyl” are usedinterchangably herein. Lower alkyl substituents include branched orunbranched C₁-C₄ alkyl groups such as methyl, ethyl, etc. Branched orunbranched C₁-C₁₀ alkyl or alkylaryl may be substituted, i.e. one ormore of the hydrogens may be replaced with a non-hydrogen atom orchemical group, for example, with other alkyl groups such as loweralkyls, phenyl, etc.

Exemplary substituents R₁, R₂ and X of generic Formula 2 are as given inTable 1 where “Compound Number” refers to the number assigned to thecompound in the synthesis schemes described in the Examples section.

TABLE 1 Examples of R₁, R₂ and X Substituents Compound Number R₁ R₂ X [5] —H —H —CH₂— [23] —CH₂CH₂CH₂Ph —H —CH₂— [17] —OCH₃ —H —CH₂— [21]—CH₂(CH₂)₄CH₃ —H —CH₂—  [17a] —OH —H —CH₂— [25] —Ph —H —CH₂—  [6] —H—CH₃ —CH₂—  [7] —H —CH₂Ph —CH₂— [22] —CH₂CH₂CH₂Ph —CH₂Ph —CH₂— [16]—OCH₃ —CH₂Ph —CH₂— [20] —CH₂(CH₂)₄CH₃ —CH₂Ph —CH₂— [18] —OH —CH₂Ph —CH₂—[12] —H —H —C(CH₃)₂— [30] —H —H —O— [36] —H —H —S—

The simplest “least substituted” compound of the present invention isspiro[9,10-dihydroanthracene]-9,3′-pyrrolidine [5] (SPAN), the formulafor which is given in Formula 3.

In compound [5], the synthesis of which is described in Example 1, R₁and R₂ are both —H and X is —CH₂—. The other compounds of the inventionare generally substituted with more complex chemical groups (i.e. withchemical groups composed of more atoms) and thus may be considered asderivatives or analogs of [5]. By “derivatives” or “analogs” we meanthat the other compounds of the invention have the basic chemicalstructure of compound [5] but contain different chemical groups at oneor more of positions R₁, R₂ and X.

The compounds of the present invention are ligands of (i.e. bind to)serotonin receptors 5-HT₂ and 5-HT_(2A) and 5-HT_(2C). By “highaffinity” we mean that the compounds display a Ki in the range of aboutless than 1 to about 500 nM. In contrast, compounds with low or moderateaffinities diplay Ki values in the range of about 2000 to about 10,000nM, and about 500 to about 2000 nM, respectively. For example, compound[5] displays a Ki of 4nM for 5-HT₂ receptors and a Ki of 24 nM for thestructurally related 5-HT_(2c) receptor and is therefore a high affinityligand for both receptors.

In addition, the compounds of the present invention are selective for5HT₂ serotonin receptors 5-HT₂, 5-HT_(2A) and 5-HT_(2C). By “selective”we mean that the affinity of the compounds for serotonin receptors issignificantly higher than for other related receptor types. For example,a compound with low selectivity typically has an affinity of about10-fold or less higher than for other related receptor types, whereasmoderately and highly selective compounds display about 10-100 fold andabout 100 to 10,000 fold higher affinities, respectively. By “relatedreceptor types” we mean other receptors implicated in the most serousside effects of typical 5HT₂ antagonists, e.g. the D2 receptor, and theserotonin and norepinephrine transporters. For example, compound [5]displays a Ki of 4 nM for the 5-HT₂ receptor and a Ki of 24 nM for thestructurally related 5-HT_(2c) receptor but is essentially devoid ofbinding activity for the dopamine D2 receptor (Ki=5040 nM), theserotonin transporter (Ki>10,000 nM) and the norepinephrine transporter(Ki>10,000 nM).

The compounds of the present invention are useful in treating a varietyof disorders that result from abnormal serotonin activity. They may beused as prophylactic and/or acute-phase remedies for the relief andreversal of serotonin-regulated symptoms. In particular, disorders thatresult from an increased synaptic concentration of serotonin, inparticular as found in depressive disorders, and that can be amelioratedby inhibition of the 5HT₂ serotonin receptors. Examples of suchconditions include but are not limited to clinical depression oranxiety, schizophrenia, schizoaffective disorder, and various eating andsleeping disorders.

The present invention also encompasses a pharmaceutical preparationcomprising at least one compound of the present invention together witha pharmaceutically acceptable carrier. The compounds of the inventioncan be used either as the free base or as the pharmaceuticallyacceptable acid-addition salt form, for example, hydrochloride,hydrobromide, tartrate, and maleate. Such a pharmaceutical preparationmay be in any of many forms suitable for administration of drugs,including but not limited to injectable dosage forms and solid dosageforms such as tablets, capsules, and the like. The compounds can beadministered in the pure form or in a pharmaceutically acceptableformulation including suitable elixirs, binders, and the like, or aspharmaceutically acceptable salts or other derivatives. It should beunderstood that the pharmaceutically acceptable formulations and saltsinclude liquid and solid materials conventionally utilized to prepareinjectable dosage forms and solid dosage forms such as tablets andcapsules. Water may be used for the preparation of injectablecompositions which may also include conventional buffers and agents torender the injectable composition isotonic. Other potential additivesinclude: colorants; surfactants (TWEEN, oleic acid, etc.); and bindersor encapsulants (lactose, liposomes, etc). Solid diluents and excipientsinclude lactose, starch, conventional disintergrating agents, coatingsand the like. Preservatives such as methyl paraben or benzalkoniumchloride may also be used. Depending on the formulation, it is expectedthat the active composition will consist of 1-99% of the composition andthe vehicular “carrier” will constitute 1-99% of the composition. Thepharmaceutical compositions of the present invention may include anysuitable pharmaceutically acceptable additives or adjuncts to the extentthat they do not hinder or interfere with the therapeutic effect desiredof agent.

The invention further provides a method for treating clinical disordersresulting from aberrant serotonin activity in a patient in need of suchtreatment. According to the method, at least one compound of the presentinvention is administered to the patient in a quantity sufficient toameliorate symptoms of such disorders.

Those of skill in the art will recognize that the exact dosage of anagent to be so-administered may vary depending on factors such as theage, gender, weight and overall health status of the individual patient,as well as on the nature of the disorder being treated. Generally,dosages in the range of from about 0.1 to about 1000 mg active agent/kgbody weight/24 hr., and more preferably about 1.0 to about 500.0 mgactive agent/kg body weight/24 hr., and even more preferably about 10 toabout 100.0 mg active agent/kg body weight/24 hr., are effective. Thelevel of efficacy and optimal amount of dosage for any given compoundmay vary from compound to compound.

The agents of the present invention may be administered by any of a widevariety of means which are well known to those of skill in the art,(including but not limited to intravenously, intramuscularly,intraperitoneallly, orally, rectally, intraocularly, and the like) or byother routes (e.g. transdermal, sublingual, aerosol, etc.). and may bein any form (e.g. liquid, solid, etc.) which is suitable for the meansof administration. Further, the agents may be administered either aloneor together with other medications in a treatment protocol.

Further, several of the compounds (e.g. [5], [16], [17], [30] and [36]of the present invention also display a high affinity for the histamineH1 receptor, high affinity being defined herein as displaying a Ki valueof about 100 nm or less. This receptor is known to function in allergicreactions in the periphery and regulation of sleep in the centralnervous system. Thus, compounds of the present invention may also beutilized to treat conditions in which it is desirable to antagonize theaction of histamine at Hi receptors. Examples of such conditions includebut are not limited to sleep disorders and allergic reactions.

Finally, the compounds of the present invention may be used as above fordetermining 5-HT₂ receptor family function, for example, in a laboratoryor clinical diagnostic setting.

EXAMPLES Example 1 Synthesis ofSpiro[9,10-dihydroanthracene-]9,3′-pyrrolidine [5] (SPAN)

The synthesis of SPAN was carried out as depicted in Scheme 1 and asfurther described below. Referring to Scheme 1, reagents and conditionswere as follows: (a) POCl₃, reflux, 45 min, (b) C₂H₅ONa, BrCH₂COOC₂H₅,EtOH, reflux, (c) 10% Pd/C, CH₃OH, HCl, (d) Borane-THF/THF; 6.0M HCl.

9-Cyano-9,10-dihydroanthracene [2]

POCl₃ (5.5 mL, 59 mmol) was added to crystalline 9,10-dihydroanthracenecarboxamide [1] (0.54 g, 2.43 mmol) while stirring. The solution wasthen heated at reflux (45 min), when TLC showed complete absence ofstarting material. The solution was then poured into a mixture ofcrushed ice and NH₄OH with vigorous stirring. The solution was stirred(15 min) and excess of NH₄OH was added to keep the solution alkaline.The solid formed was extracted with ether (3×50 ml). The combined etherextracts were washed with water and brine, dried (MgSO₄) and evaporatedunder reduced pressure to give an yellow oil which crystallizedimmediately. The product was purified by mplc using pet. ether: acetone(9:1) as eluent to give 0.296 g (60%) of pure9-Cyano-9,10-dihydroanthracene as colorless crystals mp. 106-108° C.**lit. mp. 101-102° C. IR^(cm−1) 2215. ¹H NMR (CDCl₃)d: 3.87-3.93 (d,J=18 Hz, 1H, CH₂), 4.05-4.11 (d, J=18 Hz, 1H, CH₂), 5.02 (s, 1H, CH),7.28-7.79 (m, 8H, Ar—H). ¹³C NMR (CDCl₃) d: 36.14, 37.60, 119.54,125.88, 127.12, 127.60, 128.53, 128.82, 129.56, 131.34, 136.65

(9-Cyano-9,10-dihydro-anthracen-9-yl)-acetic acid ethyl ester [3]

9-Cyano-9,10-dihydroanthracene [2] (1.25 g, 6.09 mmol) was added tosodium ethoxide prepared from Na (0.196 g, 8.53 mmol) and EtOH (10 mL)and heated at reflux (1 hr). The solution was then cooled in an ice bathand ethyl bromoacetate (1.42 g, 8.53 mmol) was added drop wise via asyringe. The resulting mixture was heated at reflux (4 h) cooled andfiltered. The residue was washed with ether (25 mL). Water (25 mL) wasadded to the filterate and the organic layer was separated. The aqueouslayer was once again extracted with ether (25 mL). The combined etherextracts were washed with water and brine, dried (MgSO₄) and evaporatedunder reduced pressure to give an oil which was purified by mplc usingpet. ether: EtOAc (9:1) as eluent to give 1.245 g (70%) of the productas a colorless oil, which crystallized on prolonged standing: mp 69-70°C. (EtOAc-pet. ether). ¹H NMR (CDCl₃)d: 1.10-1.15 (t, J=7.5 Hz, CH₃),2.85 (s, 2H, CH₂), 3.97-4.14 (m, 4H, CH₂), 7.33-7.89 (m, 8H, Ar—H). ¹³CNMR (CDCl₃)d: 14.53, 35.27, 46.05, 46.28, 61.63, 121.89, 127.58, 127.70,128.93, 134.21, 135.10, 167.96

Spiro [9,10-dihydroanthracene]-9,4′-pyrrolidin-2′-one [4]

A mixture of (9-Cyano-9,10-dihydro-anthracen-9-yl)-acetic acid ethylester [3] (0.60 g, 2.061 mol), 10% Pd/C (0.15 g) in methanol (40 mL) andHCl (1 mL) was hydrogenated at 50 kg/cm³ (3 days). The catalyst wasfiltered off with celite and the solvent was evaporated under reducedpressure to give a white semisolid. Water (25 mL) was added and thesolution was made basic with 10% NaOH and extracted with EtOAc (3×25mL). The combined EtOAc extracts were washed with water and brine, dried(MgSO₄) and evaporated under reduced pressure to give a colorless oilwhich crystallized immediately on standing. The solid was recrystallizedfrom CHCl₃-pet.ether to give 0.35 g (68%) of the pure amide as a whitecrystalline solid: mp 189-190° C. ¹H NMR (CDCl₃)d: 3.06 (s, 2H, CH₂),3.70 (s, 2H, CH₂), 4.00-4.06 (d, J=18 Hz, 1H, CH₂), 4.09-4.15 (d, J=18Hz, 1H, CH₂), 6.15 (s, 1H, NH), 7.24-7.58 (m, 8H, Ar—H). ¹³C NMR(CDCl₃)d: 36.37, 43.20, 47.49, 55.66, 125.04, 127.50, 128.73, 136.35,141.36, 178.40

Spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine [5]

A 1.0 M solution of BH₃-THF complex (7.00 ml, 7.00 mmol) was added at 0°C. to a well stirred solution of4-Spiro-9-(9,10-dihydroanthracene)pyrrolidin-2-one [4](0.35 g, 1.40mmol) in anhydrous THF (2 mL). The solution was brought to RT and thenheated at reflux (8 h), cooled to RT and 6 M solution of HCl (4 mL) wasadded cautiously to the reaction mixture. The reaction mixture was thenheated at reflux (1 hr), cooled to RT and the solvent was removed underreduced pressure, resulting in a white suspension. Water (20 mL) wasadded to it and extracted with EtOAc (20 mL). The aqueous phase was thenbasified using 10% NaOH and extracted with Et₂O (3×25 ml). The combinedEt₂O extracts were washed with water and brine, dried (MgSO₄) and thesolvent was removed under reduced pressure to give 0.31 g (94%) theamine as colorless oil. The oil started to darken rapidly and wasdissolved in anhydrous acetone and fumaric acid (0.15 g, 1.31 mmol) wasadded and heated. The solution on cooling gave the fumarate as pale pinkpowder, which remained on two recrystallizations. mp. 190.5-191.5° C.(EtOAc—CH₃OH). ¹H NMR (DMSO-d₆)d: 2.25-2.30 (t, J=7.5 Hz, 2H, CH₂),3.21-3.26 (t, J=7.5 Hz, 2H, CH₂), 3.55 (s, 2H, CH₂), 4.06 (s, 2H, CH₂),6.44 (s, 1H, fumarate), 7.20-7.56 (m, 8H, Ar—H). ¹³C NMR (DMSO-d₆)d:36.22, 36.67, 45.18, 51.09, 54.10, 124.43, 126.69, 126.76, 128.17,135.84, 137.08, 141.44, 168.96. Anal. Calcd. For (C₁₇H₁₇N.½C₄H₄O₄): C,77.79; H, 6.52; N, 4.77. Found. C, 77.12; H, 6.56; N, 4.78

Example 2 Synthesis ofSpiro[9,10-dihydroanthracene]-9,3′-(1-methyl)-pyrrolidine [6]

The synthesis of compound [6] was carried out as depicted in Scheme 2and as described below. Referring to Scheme 2, reagents and conditionswere as follows: (a) NaCNBH₃/CH₃CN.

Spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine [5] (0.23 g, 1.0 mmol)was dissolved in a mixture of anhydrous CH₃CN (10 mL) and formaldehyde(37%, 0.5 mL). NaCNBH₃ (0.10 g, 1.6 mmol) was added in portions over 5min. and the reaction mixture was stirred (45 min) at room temperature.Glacial acetic acid was added dropwise until the solution testedneutral. Stirring was continued for another 45 min, glacial acetic acidbeing added occasionally to maintain pH. The solvent was removed underreduced pressure and 2 N NaOH (20 mL) was added and extracted with Et₂O(2×25 mL). The combined Et₂O extracts were then extracted with 1N HCl(3×25 mL). The acid extracts were combined and neutralized with solidNaOH and extracted with Et₂O (3×25 mL). The combined Et₂O extracts werewashed with water, brine, dried (MgSO₄) and evaporated under reducedpressure to give 0.155 g (63%) of colorless oil. The oil was dissolvedin anhydrous acetone and fumaric acid (0.079 g, 0.68 mmol) was added andheated to dissolve the acid. The solution on cooling the product as awhite powder: mp. 162-163° C. (EtOAc—CH₃OH). ¹H NMR (DMSO-d₆)δ:2.39-2.44 (t, J=7.5 Hz, 2H, CH₂), 2.46 (s, 3H, CH₃), 3.00-3.04 (t, J=6Hz, 2H, CH₂), 3.11 (s, 2H, CH₂), 4.02 (s, 2H, CH₂), 6.59 (s, 1H,fumarate), 7.18-7.62 (m, 8H, Ar—H). ¹³C NMR (DMSO-d₆) δ: 35.77, 38.50,42.20, 49.94, 55.85, 67.28, 125.43, 126.39, 126.56, 127.89, 134.56,136.19, 143.03, 166.67. Anal. Calcd. For (C₁₈H₁₉N.C₄H₄O₄.0.25H₂O): C,71.42; H, 6.40; N, 3.78. Found. C, 71.68; H, 6.68; N, 3.75

Example 3 Synthesis ofSpiro[9,10-dihydroanthracene]-9,3′-(1-benzyl)-pyrrolidine [7]

The synthesis of compound [7] was from [5] was carried out as depictedin Scheme 3 and as described below. Regarding Scheme 3, reagents andconditions were as follows: C₆H₅CH₂Br, Et₃N, CH₂Cl₂, reflux.

Spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine [5] (0.125 g, 0.53 mmol)was dissolved in anhydrous CH₂Cl₂ ( 10 mL) and triethylamine was addeddropwise. The reaction mixture was cooled in an ice-bath and benzylbromide (0.113 g, 0.66 mmol) in anhydrous CH₂Cl₂ (5 mL) was added viasyringe. The reaction mixture was warmed to room temperature and thenheated at reflux (4 h). The solvent was removed under reduced pressureand water (20 mL) was added to the residue and extracted with EtOAc(3×25 mL). The combined EtOAc extracts were washed with water, brine,dried (MgSO₄) and evaporated under reduced pressure to give a dark brownoil which was purified by mplc using CH₂Cl₂ as eluent to give 0.12 g(70%) of the amine as a colorless oil. The oil was dissolved inanhydrous acetone and fumaric acid (0.047 g, 0.40 mmol) was added andheated to dissolve the acid. The solution on cooling gave the product asa white powder: mp. 175-176° C. (EtOAc—CH₃OH). ¹H NMR (DMSO-d₆)δ:2.31-2.35 (t, J=6 Hz, 2H, CH₂), 2.87-2.92 (t, J=7.5 Hz, 2H, CH₂), 3.02(s, 2H, CH₂), 3.74 (s, 2H, CH₂), 3.98 (s, 2H, CH₂), 6.61 (s, 1H,fumarate), 7.14-7.66 (m, 8H, Ar—H). ¹³C NMR (DMSO-d₆) δ: 35.56, 49.22,53.81, 59.68, 66.15, 125.67, 126.19, 126.53, 127.28, 127.78, 128.60,128.81, 134.40, 135.83, 143.92, 166.39. Anal. Calcd. For(C₂₄H₂₃N.C₄H₄O₄): C, 76.16; H, 6.16; N, 3.17. Found. C, 76.08; H, 6.25;N, 3.21

Example 4 Synthesis ofSpiro[-(10,10-dimethyl)-9,10-dihydroanthracene]-9,3′-pyrrolidine [12]

Compound 12 was synthesized as depicted in Scheme 4 and as describedbelow. Referring to Scheme 4, reagents and conditions were as follows:(a) POCl₃, reflux, 45 min, (b) C₂H₅ONa, BrCH₂COOC₂H₅, EtOH, reflux, (c)10% Pd/C, CH₃OH, HCl, (d) Borane-THF/THF; 6.0M HCl.

9-cyano-10,10-Dimethyl-9,10-dihydroanthracene [9]

POCl₃ (25 mL, 00 mmol) was added to crystalline10,10-Dimethyl-9,10-dihydroanthracene-9-carboxamide [8] (1.25 g, 4.9mmol) while stirring. The solution was then heated at reflux (30 min),when TLC showed complete absence of starting material. The solution wasthen poured into a mixture of crushed ice and NH₄OH with vigorousstirring. The solution was stirred for 15 minutes and excess of NH₄OHwas added to keep the solution alkaline. A solid substance separated outwhich was extracted with ether (3×50 ml). The combined ether extractswere washed with water, brine, dried (MgSO₄) and evaporated underreduced pressure to give an light yellow oil which crystallizedimmediately. The product obtained was chromatographically pure andrecrystallized readily from EtOH to give 1.0 g (86%) of the product ascolorless prisms. mp. 91-92° C. ¹H NMR (CDCl₃)d: 1.54 (s, 3H, CH₃), 1.79(s, 3H, CH₃), 5.32 (s, 1H, CH), 7.32-7.68 (m, 8H, Ar—H). ¹³C NMR(CDCl₃)d: 30.22, 30.33, 36.95, 125.77, 127.43, 127.92, 129.28. Anal.Calcd. For (C₁₇H₁₅N): C, H, N.

(9-Cyano-10,10-dimethyl-9,10-dihydro-anthracen-9-yl)-acetic acid ethylester [10]

9-cyano-10,10-Dimethyl-9,10-dihydroanthracene [9] (0.8 g, 3.42 mmol) wasadded to sodium ethoxide prepared from Na metal (0.110 g, 4.80 mmol) andethanol (10 mL) and heated under reflux for one hour leading to thedevelopment of a greenish brown solution. The solution was then cooledin an ice bath and ethyl bromoacetate (0.80 g, 4.80 mmol) was addeddropwise via a syringe. The resulting mixture was then heated at reflux(4 h) and filtered. The solid residue was washed with ether (25 mL).Water (25 mL) was added to the filterate and the organic layer wasseparated. The aqueous layer was once again extracted with ether (25mL). The combined ether extracts were washed with water, brine, dried(MgSO₄) and evaporated under reduced pressure to give an oil which waspurified by medium pressure liquid chromatography using pet. ether:EtOAc (9:1) as eluent to give 0.978 g (74%) of the product as acolorless oil. ¹H NMR (CDCl₃)d: 0.98-1.06 (t, 3H, CH₃), 1.64-1.67 (d,J=9Hz, 3H, CH₃), 1.71-1.74 (d, J=9 Hz, 3H, CH₃), 3.04-3.07 (d, J=9Hz,2H, CH₂), 3.86-3.94 (q, 2H, CH₂), 7.29-7.77 (m, 8H, Ar—H). ¹³C NMR(CDCl₃)d: 14.39, 33.85, 35.21, 38.37, 52.29, 61.38, 123.17, 127.53,127.84, 128.17, 129.48, 130.97, 143.23, 167.97.

Spiro[-(10,10-dimethyl)-9,10-dihydroanthracene]-9,4′-pyrrolidin-2′-one[11]

A mixture of(9-Cyano- 10,10-dimethyl-9,10-dihydro-anthracen-9-yl)-aceticacid ethyl ester [10] (0.975 g, 3.05 mol), 10% Pd/C (0.1 g) in methanol(20 mL) and HCl (1 mL) was hydrogenated at 50 kg/cm³ (24 h). Thecatalyst was filtered off with celite and the solvent was evaporatedunder reduced pressure to give a white semisolid. Water (25 mL) wasadded and the solution was made basic with 10% NaOH and extracted withEtOAc (3×25 mL). The combined EtOAc extracts were washed with water,brine and dried using anhydrous MgSO₄ and evaporated under reducedpressure to give a colorless oil which was purified by mplc usingpet.ether: EtOAc (8:2) as eluent to give a white solid. The solid wasrecrystallized from CHCl₃-pet.ether to give 0.4 g (40%) of the pureamide as colorless needles. mp 236-237° C. ¹H NMR (CDCl₃)d: 1.68 (s, 6H,CH3), 3.07 (s, 2H, CH₂), 3.97 (s, 2H, CH₂), 7.32-7.56 (m, 8H, Ar—H). ¹³CNMR (CDCl₃)d: 35.17, 35.26, 37.89, 43.67, 53.34, 63.86, 126.68, 126.98,127.70, 128.00, 141.14, 142.47, 178.04

Spiro[-(10,10-dimethyl)-9,10-dihydroanthracene]-9,3′-pyrrolidine [12]

A 1.0M solution of BH₃-THF complex (7.00 ml, 7.00 mmol) was added at 0°C. to a well stirred solution ofSpiro[-(10,10-dimethyl)-9,10-dihydroanthracene]-9,4′-pyrrolidin-2′-one[11] (0.15 g, 0.54 mmol) in anhydrous THF (2 mL). The solution wasbrought to room temperature and then heated at reflux (8 h), cooled and6 M solution of HCl (4 mL) was added cautiously to the reaction mixture.The reaction mixture was then heated at reflux for an additional hour,cooled and the solvent was removed under reduced pressure, resulting ina white suspension. Water (20 mL) was added to it and extracted withEtOAc (20 mL). The aqueous phase was then basified using 10% NaOH andthe resultant solution was extracted with Et₂O (3×25 ml). The combinedEt₂O extracts were washed with water, brine, dried (MgSO₄) and thesolvent was removed under reduced pressure to give 0.129 g (90%) theamine as a colorless oil. The oil was dissolved in anhydrous acetone andfumaric acid (0.062 g, 0.538 mmol) was added and heated. The solution oncooling gave the fumarate as a white powder: mp. 207-208° C.(EtOAc—CH₃OH). ¹H NMR (DMSO-d₆)d: 1.57 (s, 3H, CH₃), 1.63 (s, 3H, CH₃),2.31-2.36 (t, J=7.5 Hz, 2H, CH₂), 3.51-3.56 (t, J=7.5 Hz, 2H, CH₂), 3.63(s, 2H, CH₂), 6.53 (s, 1H, fumarate), 7.27-7.64 (m, 8H, Ar—H). ¹³C NMR(DMSO-d₆) δ: 33.77, 35.19, 37.67, 47.00, 48.70, 48.88, 63.75, 126.70,127.17, 135.39, 140.55, 142.59, 168.28. Anal. Calcd. For(C₁₉H₂₁N.C₄H₄O₄): C, 72.80; H, 6.64; N, 3.69. Found C, 72.40, 6.64, 3.65

Example 5 Synthesis ofSpiro[-(3-methoxy)-9,10-dihydroanthracene]-9,3′-pyrrolidine [17]

The compound [17] was synthesized as depicted in Scheme 5 and describedbelow. Referring to Scheme 5, reagents and conditions were as follows:(a) 2-Bromobenzaldehyde, anhydrous THF, 0° C. (b) LiAlH₄/AlCl₃,anhydrous Et₂O, reflux (c) n-BuLi, anhydrous Et₂O,n-benzyl-3-pyrrolidone (d) CH₃SO₃H, rt (e) 10% Pd/C, CH₃OH.

(2-Bromo-phenyl)-(3-methoxy-phenyl)-methanol [13]

3-Methoxyphenyl magnesium bromide (1.0 M solution in THF; 5.4 mL, 5.4mmol) was taken in a flask under N₂ and cooled (0° C.).2-Bromobenzaldehyde (1 g, 5.4 mmol) in anhydrous THF (10 mL) was addeddropwise via syringe over 5 min. The reaction mixture was stirred atthis temperature for 20 min. and slowly brought to room temperature.After stirring for another 30 min. satd. NH₄Cl solution (20 mL) wasadded and the mixture was extracted with Et₂O (3×25 mL). The combinedEt₂O extracts were washed with water, brine, dried (MgSO₄) andevaporated under reduced pressure to give a yellow oil. The oil waspurified by mplc using CH₂Cl₂ as eluent to give 1.275 g (81%) of thealcohol as a colorless oil. ¹H NMR (CDCl₃)d: 2.71 (s, 1H, OH), 3.78 (s,3H, CH₃), 6.15 (s, 1H, CH), 6.80-7.58 (m, 8H, Ar—H). ¹³C NMR (CDCl₃)d:55.80, 75.16, 113.29, 119.90, 123.39, 128.33, 129.11, 129.71, 130.08,133.39.

3-(2-Bromobenzyl)-methoxy benzene [14]

LiAlH₄ (0.154 g, 4.06 mmol) was suspended in anhydrous Et₂O (10 mL)under a N₂ atmosphere and cooled (0° C.) with stirring. Anhydrous AlCl₃(1.08 g, 8.14 mmol)was dissolved in ice-cold anhydrous Et₂O (20 mL) andadded dropwise to the LiAlH₄ suspension. After complete addition thesuspension was stirred at the same temperature (20 min.).(2-Bromo-phenyl)-(3-methoxy-phenyl)-methanol [13] (0.68 g, 2.32 mmol)was dissolved in anhydrous Et₂O (10 mL) and added dropwise via syringeto the suspension. After complete addition the reaction mixture washeated at reflux (4 h), cooled (0° C.) and EtOAc was added dropwise todestroy the excess of the reagent and the mixture was added to 20% aq.H₂SO₄ (50 mL). Et₂O (50 mL) was added and extracted. The Et₂O layer wasseparated, washed with water, brine, dried (MgSO₄) and evaporated togive a reddish yellow oil. The oil was purified by mplc using pet.ether-CH₂Cl₂ (9:1) as eluent to give 0.485 g (75%) of the pure productas a colorless oil. ¹H NMR (CDCl₃)d: 3.81 (s, 3H, CH₃), 4.14 (s, 2H,CH₂), 6.79-7.62 (m, 8H, Ar—H). ¹³C NMR (CDCl₃)d: 42.34, 55.69, 112.07,122.02, 125.48, 128.07, 128.50, 130.02, 131.66, 133.43.

1-Benzyl-3-[2-(3-methoxy-benzyl)-phenyl]-pyrrolidin-3-ol [15]

3-(2-Bromobenzyl)-methoxy benzene (0.5 g, 1.80 mmol) [14] was dissolvedin anhydrous Et₂O (15 mL)and cooled to −78° C. under N₂. n-butyl lithium(0.8 mL, 1.98 mmol, 2.5M soln. in Et₂O) was added dropwise over 5 min.and stirred for 30 min. The reaction mixture was then brought to roomtemperature over 1 hr. The reaction mixture was cooled to −78° C. andn-benzyl-3-pyrrolidone (0.31 mL, 1.9 mmol) in anhydrous Et₂O (5 mL) wasadded via syringe with stirring. The reaction mixture was brought toroom temperature over 3 hr. Water (50 mL) was added and the organicphase was extracted. The aqueous phase was extracted with Et₂O (50 mL)and the combined Et₂O extracts were washed with water, brine and dried(MgSO₄). Et₂O was removed under reduced pressure to give a red oil whichwas purified by mplc using CH₂Cl₂:(CH₃)₂CO (9:1) as eluent to give 0.3 g(45%) of the aminoalcohol as a dark yellow oil. A small sample wasconverted into its filmarate, mp 148-149° C. (EtOAc—CH₃OH). ¹H NMR(DMSO-d₆)d: 2.11-2.40 (m, 2H, CH₂), 2.96-2.99 (d, 4H, CH₂), 3.23-3.27(d, 1H, OH), 3.67 (s, 3H, CH₃), 3.89 (s, 2H, CH₂), 4.27 (s, 2H, CH₂),6.58-7.42 (m, 14H, Ar—H). ¹³C NMR (CDCl₃)d: 38.21, 52.70, 55.21, 59.71,66.46, 80.27, 111.23, 115.17, 121.54, 125.84, 125.97, 127.38, 127.86,128.67, 129.38, 129.58, 132.17, 134.71, 139.49, 143.93, 159.37, 160.97.

3-Methoxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[16]

Methanesulfonic acid (5 mL) was added to1-Benzyl-3-[2-(3-methoxy-benzyl)-phenyl]-pyrrolidin-3-ol [15] (0.5 g,1.33 mmol) taken in a round bottom flask equipped with a stirrer underN₂ at room temperature. Stirring was continued (30 min.), when TLCshowed absence of starting material. Crushed ice/water was added to thereaction mixture and the solution was made basic by the addition of 10%NaOH. The alkaline reaction mixture was extracted with EtOAc (3×25 mL).The combined EtOAc extracts were washed with water, brine and dried(MgSO₄). EtOAc was removed under reduced pressure to give a red oilwhich was purified by mplc using CH₂Cl₂:(CH₃)₂CO (9:1) as eluent to give0.24 g (52%) of the amine as a colorless oil. The oil was converted intoits oxalate salt mp. 187-188° C. (Acetone). Anal. Calcd. For(C₂₅H₂₅NO.C₂H₂O₄): C, 72.79; H, 6.10; N, 3.14. Found. C, 72.75; H, 6.15;N, 3.11. ¹H NMR (DMSO-d₆)d: 2.52 (s, 2H, CH₂), 3.27 (bs, 2H, CH₂), 3.40(s, 2H, CH₂), 3.77 (s, 3H, CH₃), 4.00 (s, 2H, CH₂), 4.13 (s, 2H, CH₂)6.82-7.63 (m, 12H, Ar—H). ¹³C NMR (DMSO-d₆)d: 35.60, 48.56, 52.92,54.98, 58.54, 111.67, 112.74, 124.45, 125.75, 126.18, 127.59, 128.08,128.42, 129.57, 135.96, 137.52, 155.71, 157.52, 162.69.

3-Methoxy-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydro-anthracene [17]

3-Methoxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[16] (0.23 g, 0.647 mmol) was dissolved in CH₃OH (15 mL) and 10% Pd/C(0.050 g) was added under N₂. A few drops of HCl were added and thereaction mixture was hydrogenated on a parr-hydrogenator at 50 psiovernight and the catalyst was filtered off using celite. The filteratewas evaporated and water (15 mL) was added and basified using 10% NaOH.The basic solution was extracted with CH₂Cl₂ (2×25 mL) and the combinedextracts were washed with water, brine and dried (MgSO₄). The CH₂Cl₂ wasremoved under reduced pressure to give a yellow oil which was purifiedby mplc using CH₂Cl₂:CH₃OH (9:1) as eluent to give 0.126 g (74%) of theproduct as a colorless oil which darkened rapidly. The oil was convertedinto its oxalate salt, mp. 99-101° C. (Acetone). Anal. Calcd. For(C₁₈H₁₉NO.C₂H₂O₄.0.5(CH₃)₂CO.0.5H₂O): C, 65.63; H, 6.40; N, 3.56. Found.C, 65.39; H, 5.99; N, 3.31. ¹H NMR (CDCl₃)d: 2.32-2.38 (m, 2H, CH₂),2.97-3.02 (t, J=15 Hz, 2H, CH₂), 3.18 (bs 2H, CH₂), 3.83 (s, 3H, CH₃),4.05 (bs, 2H, CH₂), 6.79-7.77 (m, 7H, Ar—H). ¹³C NMR (CDCl₃)d: 36.75,41.94, 52.78, 55.27, 65.73, 112.93, 125.87, 126.24, 126.90, 127.47,128.01, 128.80, 129.61.

Example 6 Synthesis of3-Hydroxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[18]

Compound 18 was synthesized as depicted in Scheme 6 and described below.Referring to Scheme 6, reagents and conditions were as follows: BBr₃,CH₂Cl₂, −78° C.

To a solution of3-Methoxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[16] (0.24 g, 0.675 mmol) in anhydrous CH₂Cl₂ (10 mL) at −78° C. wasadded BBr₃ (2.70 mL, 2.7 mmol, 1M soln. in CH₂Cl₂) dropwise. Thetemperature was raised to ambient temperature over a period of 2 hr. andstirring was continued for 6 hr. The reaction mixture was cooled to −78°C. and CH₃OH (5 mL) was added dropwise via syringe and the solvent wasremoved under reduced pressure. The residue was redissolved in CH₃OH andsatd. Solution of NaHCO₃ was added and extracted with Et₂O (2×25 mL).The combined Et₂O extracts were washed with water, brine and dried(MgSO₄). The solvent was removed under reduced pressure to give a darkyellow oil. The oil was purified by mplc using CH₂Cl₂:(CH₃)₂CO (9:1) aseluent to give 0.21 g (91%) the product as a pale yellow oil. The oilwas converted into its oxalate salt mp. 133-134° C. (EtOAC—CH₃OH). Anal.Calcd. For (C₂₄H₂₃NO.C₂H₂O₄.0.5H₂O): C, 70.89; H, 5.94; N, 3.17. Found.C, 70.90; H, 5.88; N, 3.30. ¹H NMR (DMSO-d₆)d: 2.50 (bs, 2H, CH₂), 3.30(bs, 2H, CH₂), 3.42 (bs, 2H, CH₂), 3.91 (bs, 2H, CH₂), 4.17 (bs, 2H,CH₂), 6.65-7.57 (m, Ar—H, 12H). ¹³C NMR (DMSO-d₆)d: 36.41, 49.40, 53.69,59.25, 64.40, 113.81, 115.09, 127.08, 129.34, 130.77, 132.40, 137.05,138.24, 142.73, 156.49, 164.15, 208.92.

Example 7 Synthesis ofSpiro[-(3-hydroxy)-9,10-dihydroanthracene]-9,3′-pyrrolidine [19]

Compound [19] was synthesized as depicted in Scheme 7 and describedbelow. Referring to Scheme 7, reagents and conditions were as follows:BBr₃, CH₂Cl₂, −78° C.

Spiro[-(3-methoxy)-9,10-dihydroanthracene]-9,3′-pyrrolidine [17] (0.2 g,0.756 mmol) was dissolved in anhydrous CH₂Cl₂ (10 mL) and cooled to −78°C. under N₂. BBr₃ (3.78 mL, 1.0M soln. in CH₂Cl₂) was added dropwise viasyringe over 15 min. The reaction mixture was allowed to stir at roomtemperature overnight and cooled to −78° C. Anhydrous CH₃OH (5 mL)wasadded dropwise and the solvents were evaporated under reduced pressureto give a dry solid. The solid was redissolved in anhydrous CH₃OH (5 mL)and EtOAc (35 mL) was added and cooled. The product crystallized as apale white solid, which was once again recrystallized from EtOAc—CH₃OHto give 0.15 g (60%) of the product as its hydrobromide, mp. 150-151° C.(dec.). ¹H NMR (DMSO-d₆)d: 2.32-2.36 (t, J=6 Hz, 2H, CH₂), 3.39 (bs, 2H,CH₂), 3.71 (bs, 2H, CH₂), 3.99 (bs, 2H, CH₂), 6.65-7.54 (m, 7H, Ar—H),9.28 (bs, 1H). ¹³C NMR (DMSO-d₆)d: 35.86, 44.43, 49.37, 51.93, 112.80,114.76, 124.76, 126.24, 126.74, 127.98, 129.50, 137.06, 138.30, 139.80,156.04, 195.17. Anal. Calcd. For (C₁₇H₁₇NO.HBr.0.5H₂O): C, 59.83; H,5.61; N, 4.10. Found. C, 59.35; H, 5.48; N, 3.60.

Example 8 Synthesis of3-n-Hexyl-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene [21]

Compound [21] was synthesized as depicted in Scheme 8 and as describedbelow. Referring to Scheme 8, reagents and conditions were as follows:(a) Triflic anhydride, C₅H₅N (b) 1-hexene, 9-BBN, PdCl₂(dppf), K₃PO₄,anhyd. THF (c) 10% Pd/C, CH₃OH, HCl.

3-Trifluoromethane sulfonyloxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [19]

To a solution of3-Hydroxy-9,9-[spiro-3′-(-benzyl)-pyrrolidinyl]-9,10-dihydro-anthracene[16] (0.765 g, 2.241 mmol) in pyridine (5 mL) at 0° C. was added triflicanhydride (0.961 g. 0.58 mL, 3.4 mmol) dropwise via syringe under N₂.The reaction mixture was gradually brought to room temperature andstirred (3 hr.). Crushed ice/water was added and the solution wasextracted with Et₂O (2×25 mL). The combined Et₂O extracts were washedwith water, brine, dried (MgSO₄) and evaporated under reduced pressureto give a red oil. The oil was purified by mplc using pet. Ether:acetone(9:1) as eluent giving 0.93 g (85%) of the triflate as a reddish brownoil. ¹H NMR (CDCl₃)d: 2.34-2.40 (m, 2H, CH₂), 2.85-2.88 (m, 2H, CH₂),2.99-3.15 (m, 2H, CH₂), 3.76 (s, 2H, CH₂), 4.02-4.05 (m, 2H, CH₂),7.13-7.84 (m, 12H, Ar—H). ¹³C NMR (CDCl₃)d: 35.43, 48.73, 53.95, 59.92,66.59, 118.58, 121.77, 126.54, 128.31, 133.85, 137.46, 142.69, 144.88,147.18

3-n-Hexyl-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[20]

An oven dried flask equipped with a septum inlet and condenser wasflushed with N₂ and charged with a soln. of 9-BBN (2.15 mL, 1.079 mmol,0.5 M soln.), cooled to 0° C. and 1-hexene (0.133 mL, 1.079 mmol) wasadded via syringe. The mixture was brought to room temperature andstirred (8 hr.). To the prepared BBN soln. was added K₃PO₄(0.312 g,1.471 mmol), PdCl₂(dppf) (0.020 g, 5 mol %) and 3-Trifluoromethanesulfonyloxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [19](0.48 g, 0.980 mmol) in anhydrous THF (10 mL). The reaction mixture washeated at reflux overnight, cooled and water (20 mL) was added. Thereaction mixture was then extracted with EtOAc (3×25 mL). The combinedEtOAc extracts were washed with water, brine and dried (MgSO₄). Thesolvent was removed under reduced pressure to give a dark brown oil,which was purified by mplc using pet. Ether-EtOAc (9:1) as eluent togive 0.34 g (85%) of the product as an yellow oil. The oil was convertedinto its oxalate, mp. 135-136° C. (EtOAc—CH₃OH). ¹H NMR (CDCl₃)d:0.872.34-2.40 (bm, 13H, CH₂), 2.30-2.42 (bm, 2H, CH₂), 2.62 (bs, 2H,CH₂), 2.93 (bs, 2H, CH₂), 3.13 (bs, 2H, CH₂), 3.75 (bs, 2H, CH₂), 4.00(bs, 2H, CH₂), 7.04-7.72 (m, 12H, Ar—H). ¹³C NMR (CDCl₃)d: 27.19, 28.87,35.62, 35.77, 41.37, 48.69, 54.26, 60.14, 67.07, 111.26, 123.54, 125.55,126.06, 126.58, 127.24, 128.02, 128.37, 134.70, 134.77, 135.04, 139.33,139.55, 140.14, 140.32, 142.28, 144.18. Anal. Calcd. For (C₃₀H₃₅N.C₂H₂O₄.0.5H₂O): C, 75.56; H, 6.52; N, 2.75. Found. C, 75.04; H, 6.76; N,2.91.

3-n-Hexyl-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene [21]

3-n-Hexyl-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[20] (0.20 g, 0.488 mmol) was dissolved in CH₃OH (15 mL) and 10% Pd/C(0.050 g) was added under N₂. A few drops of HCl were added and thereaction mixture was hydrogenated on a parr-hydrogenator at 50 psiovernight and the catalyst was filtered off using celite. The filteratewas evaporated and water (15 mL) was added and basified using 10% NaOH.The basic solution was extracted with CH₂Cl₂ (2×25 mL) and the combinedextracts were washed with water, brine and dried (MgSO₄). The CH₂Cl₂ wasremoved under reduced pressure to give a yellow oil which was purifiedby mplc using CH₂Cl₂:CH₃OH (9:1) as eluent to give 0.11 g (70%) of theproduct as a colorless oil which darkened rapidly. The oil was convertedinto its oxalate salt, mp. 110-111° C. (EtOAc—CH₃OH). ¹H NMR (CDCl₃)d:0.83-0.89 (m, 2H, CH₂), 1.21-1.31 (m, 9H, CH₂), 2.36-2.40 (t, J=6 Hz,2H, CH₂), 2.56-2.61 (t, J=6 Hz, 2H, CH₂), 3.49 (bs, 2H, CH₂), 3.74 (bs,2H, CH₂), 4.03 (bs, 2H, CH₂), 7.11-7.54 (m, 7H, Ar—H). Anal. Calcd. For(C₂₃H₂₉N.C₂H₂O₄.0.25H₂O): C, 72.52; H, 7.66; N, 3.38. Found. C, 72.29;H, 7.55; N, 3.15.

Example 9 Synthesis of3-(3-Phenylpropyl)-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene[23]

Compound [23] was synthesized as depicted in Scheme 9 and as describedbelow. Referring to Scheme 9, reagents and conditions were as follows:(a) allyl benzene, 9-BBN, PdCl₂(dppf), K₃PO₄, anhyd. THF (b) 10% Pd/C,CH₃OH, HCl

3-(3-Phenylpropyl)-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[22]

An oven dried flask equipped with a septum inlet and condenser wasflushed with N₂ and charged with a soln. of 9-BBN (2.15 mL, 1.079 mmol,0.5 M soln.), cooled to 0° C. and allyl benzene (0.142 mL, 1.079 mmol)was added via syringe. The mixture was brought to room temperature andstirred (8 hr.). To the prepared BBN soln. was added K₃PO₄ (0.312 g,1.471 mmol), PdCl₂(dppf) (0.020 g, 5 mol %) and 3-Trifluoromethanesulfonyloxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [19](0.48 g, 0.980 mmol) in anhydrous THF (10 mL). The reaction mixture washeated at reflux overnight, cooled and water (20 mL) was added. Thereaction mixture was then extracted with EtOAc (3×25 mL). The combinedEtOAc extracts were washed with water, brine and dried (MgSO₄). Thesolvent was removed under reduced pressure to give a dark brown oil,which was purified by mplc using pet. Ether-EtOAc (9:1) as eluent togive 0.22 g (52%) of the product as an yellow oil. The oil was convertedinto its oxalate, mp. 137-138° C. (EtOAc—CH₃OH). ¹H NMR (DMSO-d₆)d: 1.55(bs, 4H, CH₂), 2.47 (s, 4H, CH₂), 3.21 (s, 2H, CH₂), 3.38 (s, 2H, CH₂),3.94-3.98 (d, J=12Hz, 2H, CH₂), 4.07 (s, 2H, CH₂). ¹³C NMR (CDCl₃)d:21.61, 25.82, 31.63, 35.57, 48.63, 59.90, 61.83, 70.58, 125.40, 125.96,126.45, 127.82, 128.20, 134.73, 135.12, 137.9, 139.04,142.86, 143.77.Anal. Calcd. For(C₃₃H₃₃N.C₂H₂O₄.H₂O): C, 76.20; H, 6.76; N, 2.53. Found.C, 76.11; H, 6.54; N, 2.94.

3-(3-Phenylpropyl)-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene[23]

3-(3-Phenylpropyl)-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [22] (0.20 g, 0.451 mmol) was dissolved in CH₃OH (15mL) and 10% Pd/C (0.050 g) was added under N₂. A few drops of HCl wereadded and the reaction mixture was hydrogenated on a parr-hydrogenatorat 50 psi overnight and the catalyst was filtered off using celite. Thefilterate was evaporated and water (15 mL) was added and basified using10% NaOH. The basic solution was extracted with CH₂Cl₂ (2×25 mL) and thecombined extracts were washed with water, brine and dried (MgSO₄). TheCH₂Cl₂ was removed under reduced pressure to give a yellow oil which waspurified by mplc using CH₂Cl₂:CH₃OH (9:1) as eluent to give 0.071 g(45%) of the product as a colorless oil which darkened rapidly. The oilwas converted into its oxalate salt, mp. 81-82° C. (EtOAc—CH₃OH). ¹H NMR(DMSo-d₆)d: 1.57-1.71 (bd, 4H, CH₂), 2.38 (s, 2H, CH₂), 2.47 (s, 2H,CH₂), 3.38 (s, 2H, CH₂), 3.77 (s, 2H, CH₂), 4.07 (s, 2H, CH₂), 7.27-7.52(bm, 7H, Ar—H). Anal. Calcd. For (C₂₆H₂₇N.C₂H₂O₄.2H₂O): C, 70.12; H,6.93; N, 2.92. Found. C, 69.45; H, 6.34; N, 3.66.

Example 10 Synthesis of3-(3-Phenyl)-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene [25]

Compound [25] was synthesized as depicted in Scheme 10 and as describedbelow. Referring to Scheme 10, reagents and conditions were as follows:(a) Phenyl boronic acid, [(C₆H₅)₃P]₄Pd, K₂CO₃, anhyd. toluene (b) 10%Pd/C, CH₃OH, HCl.

3-(3-Phenyl)-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[24]

An oven dried flask equipped with a septum inlet and condenser wasflushed with N₂ phenyl boronic acid (0.25 g, 2.043 mmol)3-Trifluoromethane sulfonyloxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [19](0.48 g, 0.980 mmol) and K₂CO3(0.282 g, 2.04 mmol) were added followedby anhydrous toluene (15 mL). [(C₆H₅)₃P]₄Pd (0.035 g, 3 mol %) was addedimmediately and the reaction mixture was heated at 90° C. for 4 hr. Thereaction mixture was then cooled to room temperature and diluted withEtOAc (25 mL) and washed with satd. NaHCO₃ soln., water, brine and dried(MgSO₄). The solvent was removed under reduced pressure to give a darkbrown oil, which was purified by mplc using pet. ether as eluent to give0.235 g (58%) of the product as a colorless oil. The oil was convertedinto its oxalate, mp. 138-139° C. (EtOAc—CH₃OH). ¹H NMR (CDCl₃)d:2.33-2.44 (m, 2H, CH₂),2.46-3.17 (m, 4H, CH₂), 3.75-3.78 (d, J=9 Hz, 2H,CH₂), 4.02-4.10 (m, 2H, CH₂), 7.12-7.84 (m, 17H, Ar—H). ¹³C NMR(CDCl₃)d: 35.92, 41.66, 49.79, 54.58 60.32, 67.02. Satisfactoryelemental analyses could not be obtained.

3-(3-Phenyl)-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene [25]

3-(3-Phenyl)-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[24] (0.25 g, 0.622 mmol) was dissolved in CH₃OH (15 mL) and 10% Pd/C(0.10 g) was added under N₂. A few drops of HCl were added and thereaction mixture was hydrogenated on a parr-hydrogenator at 50 psi (4days) and the catalyst was filtered off using celite. The filterate wasevaporated and water (15 mL) was added and basified using 10% NaOH. Thebasic solution was extracted with CH₂Cl₂ (2×25 mL) and the combinedextracts were washed with water, brine and dried (MgSO₄). The CH₂Cl₂ wasremoved under reduced pressure to give a yellow oil which was purifiedby mplc using CH₂Cl₂:CH₃OH (9:1) as eluent to give 0.081 g (42%) of theproduct as a colorless oil which darkened rapidly. The oil was convertedinto its fumarate salt, mp. 129-130° C. (EtOAc—CH₃OH). ¹H NMR(DMSO-d₆)d: 2.35-2.39 (t, J=6Hz, 2H, CH₂), 3.33-3.3 (t, J=6 Hz, 2H,CH₂), 3.78 (s, 2H, CH₂), 4.02-4.04 (d, J=6 Hz, 2H, CH₂), 6.51 (s, 2H,CH═CH), 7.27-7.71 (m, 12H, Ar—H). ¹³C NMR (CDCl₃)d: 35.92, 46.92, 51.71,58.88, 123.83, 126.26, 126.87, 127.54, 128.56, 135.99, 136.83, 138.86,140.55, 141.22, 141.90. Anal. Calcd. For (C₂₃H₂₁N.C₄H₄O₄.H₂O): C, 72.16;H, 6.22; N, 3.08. Found. C, 71.62; H, 6.19; N, 2.84.

Example 11 Synthesis of Spiro[xanthenyl]-9,3′-pyrrolidine [30]

Compound [30] was synthesized as depicted in Scheme 11 and as describedbelow. Referring to Scheme 11, reagents and conditions were as follows:(a) POCl₃, reflux, 45 min, (b) n-BuLi, BrCH₂COOC₂H₅, Et₂O, reflux, (c)10% Pd/C, CH₃OH, HCl, (d) Borane-THF/THF; 6.0M HCl.

9H-Xanthene-9-carbonitrile [27]

POCl₃ (25 mL) was added to crystalline 9H-Xanthene-9-carboxamide [26](1.5 g, 6.65 mmol) while stirring. The solution was then heated atreflux (45 min), when TLC showed complete absence of starting material.The solution was then poured into a mixture of crushed ice and NH₄OHwith vigorous stirring. The solution was stirred (15 min) and excess ofNH₄OH was added to keep the solution alkaline. The solid formed wasextracted with ether (3×50 ml). The combined ether extracts were washedwith water and brine, dried (MgSO₄) and evaporated under reducedpressure to give an yellow oil which crystallized immediately. Theproduct was purified by mplc using pet. ether: acetone (8:2) as eluentto give 1.2 g (87%) 9H-Xanthene-9-carbonitrile as colorless needles, mp97-98° C. (EtOH).

(9-Cyano-9H-xanthen-9-yl)-acetic acid ethyl ester [28]

9H-Xanthene-9-carbonitrile [27] (1.0 g, 4.825 mmol) was dissolved inanhydrous Et₂O and cooled in an icebath. n-Butyl lithium (1.93 mL, 6.75mmol. 2.5M soln. in hexanes) was added dropwise over 10 min. withcontinuos stirring. Stirring was continued for 30 min. at the sametemperature and then brought to room temperature. The reaction mixturewas heated at reflux (1 hr), cooled in an icebath and ethyl bromoacetate (0.75 mL, 6.755 mmol) was added dropwise via syringe. Theresulting mixture was heated at reflux (4 h) cooled and filtered. Theresidue was washed with ether (25 mL). Water (25 mL) was added to thefilterate and the organic layer was separated. The aqueous layer wasonce again extracted with ether (25 mL). The combined ether extractswere washed with water and brine, dried (MgSO₄) and evaporated underreduced pressure to give an oil which was purified by mplc using pet.ether: EtOAc (9:1) as eluent to give 0.9 g (64%) of the product as acolorless oil. ¹H NMR (CDCl₃)d: 1.04-1.08 (t, J=7.5 Hz, CH₃), 3.01 (s,2H, CH₂), 3.90-3.99 (q, 2H, CH₂), 7.14-7.69 (m, 8H, Ar—H). ¹³C NMR(CDCl₃)d: 13.54, 39.06, 48.47, 60.85, 116.88, 118.90, 119.75, 123.81,127.34, 129.83, 150.30, 166.98.

Spiro[xanthenyl]-9,4′-pyrrolidin-2′-one [29]

A mixture of (9-Cyano-9H-xanthen-9-yl)-acetic acid ethyl ester [28](0.50 g, 1.70 mmol), 10% Pd/C (0.15 g) in methanol (40 mL) and HCl (1mL) was hydrogenated at 50 kg/cm³ (3 days). The catalyst was filteredoff with celite and the solvent was evaporated under reduced pressure togive a white semisolid. Water (25 mL) was added and the solution wasmade basic with 10% NaOH and extracted with EtOAc (3×25 mL). Thecombined EtOAc extracts were washed with water and brine, dried (MgSO₄)and evaporated under reduced pressure to give a colorless oil whichcrystallized immediately on standing. The solid was recrystallized fromCHCl₃-pet.ether to give 0.295 g (69%) of the pure amide as a colorlessneedles, mp 182-183° C. ¹H NMR (CDCl₃)d: 3.02 (s, 2H, CH₂), 3.82 (s, 2H,CH₂), 6.51 (s, 1H, NH), 7.07-7.44 (m, 8H, Ar—H). ¹³C NMR (CDCl₃)d:39.98, 48.50, 60.72, 116.39, 123.70, 125.77, 126.46, 128.31, 149.59,176.10.

Spiro[xanthenyl]-9,3′-pyrrolidine [30]

A 1.0M solution of BH₃-THF complex (5.0 ml, 5 mmol) was added at 0° C.to a well stirred solution of Spiro[xanthenyl]-9,4′-pyrrolidin-2′-one[29] (0.25 g, 0.99 mmol) in anhydrous THF (2 mL). The solution wasbrought to RT and then heated at reflux (8 h), cooled to RT and 6Msolution of HCl (4 mL) was added cautiously to the reaction mixture. Thereaction mixture was then heated at reflux (1 hr), cooled to RT and thesolvent was removed under reduced pressure, resulting in a whitesuspension. Water (20 mL) was added to it and extracted with EtOAc (20mL). The aqueous phase was then basified using 10% NaOH and extractedwith Et₂O (3×25 ml). The combined Et₂O extracts were washed with waterand brine, dried (MgSO₄) and the solvent was removed under reducedpressure to give 0.185 g (79%) the amine as colorless oil. The oilstarted to darken rapidly and was dissolved in anhydrous acetone andfumaric acid (0.15 g, 1.31 mmol) was added and heated. The solution oncooling gave the fumarate as pale pink powder, which remained on tworecrystallizations. mp. 183-184° C. (EtOAc). ¹H NMR (DMSO-d₆)d:2.26-2.31 (t, J=9 Hz, 2H, CH₂), 3.41-3.45 (t, J=6 Hz, 2H, CH₂), 3.64 (s,2H, CH₂), 6.54 (s, 2H, CH═CH), 7.11-7.64 (m, 8H, Ar—H). ¹³C NMR(DMSO-d₆)d: 44.35, 59.51, 115.96, 123.73, 126.54, 127.24, 128.22,134.87, 140.12, 141.02, 149.87, 167.74, 179.90, 186.56. Anal. Calcd. For(C₁₇H₁₇N.C₄H₄O₄.0.5H₂O): C, 66.28;H, 5.56; N, 3.86. Found. C, 66.41; H,5.59; N, 3.82

Example 12

Synthesis of Spiro[thioxanthenyl]-9,3′-pyrrolidine [36]Compound [36] wassynthesized as depicted in Scheme 12, and as described below. Referringto Scheme 12, reagents and conditions were as follows: (a) NaBH₄, CH₃OH(b) (i) SOCl₂/Et₂O (ii) CuCN/C₆H₆ (c) n-BuLi, BrCH₂COOC₂H₅, Et₂O,reflux, (c) 10% Pd/C, CH₃OH, HCl, (d) Borane-THF/THF; 6.0M HCl.

9H-Thioxanthen-9-ol [32]

A suspension of thioxanthen-9-one [31] (2 g, 9.42 mmol) in anhydrousCH₃OH (30 mL) was stirred under N₂ and NaBH₄ (1.42 g, 37.68 mmol) wasadded slowly in portions over 15 min. After complete addition thereaction mixture was heated at reflux (3 hr.) and cooled to roomtemperature. Ice-water was added and the reaction mixture was extractedwith CH₂Cl₂ (3×50 mL). The combined CH₂Cl₂ extracts were washed withwater, brine, dried (MgSO₄). The solvent was removed under reducedpressure to give a yellow solid, which was recrystallized from pet.etherto give 1.87 g (93%) of the alcohol as pale yellow needles, mp 104-105°C.

9H-Thioxanthene-9-carbonitrile [33]

A suspension of 9H-Thioxanthen-9-ol [32] (2.14 g, 9.98 mmol) inanhydrous Et₂O (20 mL) under N₂ and SOCl₂ (0.8 mL, 11.48 mmol) was addedwith caution via syringe with stirring at 0-5° C. The alcohol dissolvedbefore a white solid began to separate. After stirring (1 hr.) at roomtemperature, the solvent was removed under reduced pressure and C₆H₆ (10mL) was added and solvent removed to dryness again. All manipulationswere performed with rigorous exclusion of air. Anhydrous C₆H₆ (20 mL)and CuCN powder (1.79 g, 19.97 mmol) were added and the suspension wasstirred at reflux (4 hr.).The reaction mixture was filtered while hotand the residue was washed with hot C₆H₆ (50 mL). The filterate wasevaporated to give a crystalline residue containing thioxanthene andthioxanthen-9-one as well as the desired nitrile. One recrystallizationsfrom hexane removed thioxanthene and one recrystallizations from2-propanol removed most of the thioxanthen-9one to provide 1.3 g (59%)of the pure nitrile, mp. 97-98° C.

(9-Cyano-9H-thioxanthen-9-yl)-acetic acid ethyl ester [34]

9H-thioxanthene-9-carbonitrile [33] (1.20 g, 5.37 mmol) was dissolved inanhydrous Et₂O and cooled in an icebath. n-Butyl lithium (2.14 mL, 5.37mmol, 2.5M soln. in hexanes) was added dropwise over 10 min. withcontinuous stirring. Stirring was continued for 30 min. at the sametemperature and then brought to room temperature. The reaction mixturewas heated at reflux (1 hr), cooled in an icebath and ethyl bromoacetate (0.83 mL, 7.52 mmol) was added dropwise via syringe. Theresulting mixture was heated at reflux (4 h) cooled and filtered. Theresidue was washed with ether (25 mL). Water (25 mL) was added to thefilterate and the organic layer was separated. The aqueous layer wasonce again extracted with ether (25 mL). The combined ether extractswere washed with water and brine, dried (MgSO₄) and evaporated underreduced pressure to give an oil which was purified by mplc using pet.ether: EtOAc (9:1) as eluent to give 0.97 g (59%) of the product as acolorless oil. ¹H NMR (CDCl₃)d: 1.08-1.12 (t, J=6 Hz, CH₃), 3.08 (s, 2H,CH₂), 3.95-4.03 (q, 2H, CH₂), 7.31-8.00 (m, 8H, Ar—H). ¹³C NMR (CDCl₃)d:38.49, 47.63, 60.76, 118.91, 127.00, 127.24, 127.80, 128.15, 130.73,130.98, 167.66.

Spiro[xanthenyl]-9,4′-pyrrolidin-2′-one [35]

A mixture of(9-Cyano-9H-thioxanthen-9-yl)-acetic acidethyl ester [34](0.50 g, 1.61 mmol), 10% Pd/C (0.15 g) in methanol (40 mL) and HCl (1mL) was hydrogenated at 50 kg/cm³ (3 days). The catalyst was filteredoff with celite and the solvent was evaporated under reduced pressure togive a white semisolid. Water (25 mL) was added and the solution wasmade basic with 10% NaOH and extracted with EtOAc (3×25 mL). Thecombined EtOAc extracts were washed with water and brine, dried (MgSO₄)and evaporated under reduced pressure to give a colorless oil whichcrystallized immediately on standing. The solid was recrystallized fromCHCl₃-pet.ether to give 0.32 g (74%) of the pure amide as a white solid,mp 178-179° C. ¹H NMR (CDCl₃)d: 3.19 (s, 2H, CH₂), 3.73 (s, 2H, CH₂),6.13 (bs, 1H, NH), 7.22-7.53 (m, 8H, Ar—H). ¹³C NMR (CDCl₃)d: 49.60,53.15, 124.69, 126.68, 127.61, 133.32, 137.72, 176.06.

Spiro[thioxanthenyl]-9,3′-pyrrolidine [36]

A 1.0M solution of BH₃-THF complex (3.75 ml, 3.75 mmol) was added at 0°C. to a well stirred solution ofspiro[thioxanthenyl]-9,4′-pyrrolidin-2′-one [35](0.2 g, 0.74 mmol) inanhydrous THF (2 mL). The solution was brought to RT and then heated atreflux (8 h), cooled to RT and 6 M solution of HCl (4 mL) was addedcautiously to the reaction mixture. The reaction mixture was then heatedat reflux (1 hr), cooled to RT and the solvent was removed under reducedpressure, resulting in a white suspension. Water (20 mL) was added to itand extracted with EtOAc (20 mL). The aqueous phase was then basifiedusing 10% NaOH and extracted with Et₂O (3×25 ml). The combined Et₂Oextracts were washed with water and brine, dried (MgSO₄) and the solventwas removed under reduced pressure to give 0.092 g (49%) the amine ascolorless oil. The oil started to darken rapidly and was dissolved inanhydrous acetone and converted into its oxalate, mp. 169-170° C.(EtOAc). ¹H NMR (DMSO-d₆)d: 2.74 (bs, 2H, CH₂), 3.39 (bs, 2H, CH₂), 3.79(s, 2H, CH₂), 7.36 (bs, 4H, Ar—H), 7.65 (bs, 4H, Ar—H). ¹³C NMR(DMSO-d₆)d: 24.64, 50.02, 51.38, 124.83, 127.02, 133.32, 137.19, 163.90,185.34. Anal. Calcd. For(C₁₆H₁₅NS.C₂H₂O₄.0.25H₂): C, 62.14; H, 5.07; N,4.02. Found. C, 61.90; H, 4.92; N, 3.86

Example 13

Affinity of Compounds for 5-HT2A Serotonin Receptor

Binding assays were conducted in which the affinity of each of thecompounds of interest for the 5-HT_(2A) serotonin receptor was tested.Assays were conducted with the 5-HT_(2A) receptor in buffer consistingof 50 mM Tris-Cl, 0.5 mM EDTA, 5 mM MgCl₂, pH=7.4. The 5-HT_(2A)affinity determinations used ³H-ketanserin as the radioligand andspiperone (K_(d)=0.8 nM) as the reference compound.

Binding assays were also conducted in which the affinity of selectedcompounds of interest for the H₁ histamine receptor was tested. Assayswere conducted with the H₁ receptor in buffer consisting of 50 mMTris-Cl, 0.5 mM EDTA, pH=7.4. The H₁ determinations used ³H-pyrilamineas the radioligand with chlorpheniramine as the reference compound.

The results are given in Table 2.

TABLE 2 Affinity of Selected SPAN Derivatives for 5-HT_(2A) and H₁Receptors 5-HT_(2A) H₁ Compound Ki (nM) Ki (nM) 5 3.8 8.5 23 3.5 — 173.7 40 21 6 1600 19 9.2 — 25 18 — 6 46 — 7 220 — 22 998 — 16 1000 74 202030 — 18 330 — 12 68 — 30 40 51 36 5 6

While the invention has been described in terms of its preferredembodiments, those skilled in the art will recognize that the inventioncan be practiced with modification within the spirit and scope of theappended claims. Accordingly, the present invention should not belimited to the embodiments as described above, but should furtherinclude all modifications and equivalents thereof within the spirit andscope of the description provided herein.

REFERENCES

Bordwell, F. G., Hughes, D. L. 1983, J. Org. Chem. 48 (13) 2216-2222.

Glennon, R. A., Dukat, M., El-Bermawy, M, Law, H, de los Angeles, J,Teitler, M, King, A and Herrick-Davis, K. 1994. J. Med. Chem.37:1929-1935.

Glennon, R A, Naiman, N A, Peirson, M E, Smith, J D, Ismaiel, A M,Titeler, M and Lyon, R A. 1989. J. Med. Chem., 32:1921.

Roth, B L, Craigo, S C, Choudhary, A U, Monsma, F J, Shen, Y, Miltzer, HY, Sibley, D R. 1994, J. Pharm. Exp Ther. 268: 1403.

Vaganova, T. A., Panteluva, E. V., Tananakin, A. P., Steingarts, V. D.,Bilkis, I. I. 1994, Tetrahedron 50 (33) 10011-10020.

We claim:
 1. A compound having the formula

wherein R1 and R2 are selected from the group consisting of —H, —OH,—OCH₃, halogen, aryl, alkylaryl, and substituted or unsubstitutedbranched or unbranched C₁-C₁₀ alkyl or alkylaryl, and may be the same ordifferent, and X is selected from the group consisting of a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,and c) —SO₂—;
 2. The compound of claim 1 wherein R1 is selected from thegroup consisting of —H, —CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂)₄CH₃, phenyl, and—OH.
 3. The compound of claim 1 wherein R2 is selected from the groupconsisting of —H, —CH₃ and CH₂Ph.
 4. The compound of claim 1 wherein Xis selected from the group consisting of —CH₂—, and —C(CH₃)₂—.
 5. Acompound having the formula


6. A compound having the formula


7. A compound having the formula


8. A compound having the formula


9. A compound having the formula


10. A compound having the formula


11. A compound having the formula


12. A compound having the formula


13. A compound having the formula


14. A pharmaceutical composition comprising, a compound of formula

wherein R1 and R2 are selected from the group consisting of —H, —OH,—OCH₃, halogen, aryl, alkylaryl, and substituted or unsubstitutedbranched or unbranched C₁-C₁₀ alkyl or alkylaryl, and may be the same ordifferent, and X is selected from the group consisting of a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,and c) —SO₂—, and a pharmaceutically acceptable carrier.
 15. Thepharmaceutical composition of claim 14 wherein R1 is selected from thegroup consisting of —H, —CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂)₄CH₃ and —OH. 16.The pharmaceutical composition of claim 14 wherein R2 is selected fromthe group consisting of —H, —CH₃ and CH₂Ph.
 17. The pharmaceuticalcomposition of claim 14 wherein X is selected from the group consistingof —CH₂—, and —C(CH₃)₂—.
 18. A method of treating a condition caused byabnormal serotonin activity in a patient in need thereof, comprising thestep of administering a compound of formula

wherein R1 and R2 are selected from the group consisting of —H, —OH,—OCH₃, halogen, aryl, alkylaryl, and substituted or unsubstitutedbranched or unbranched C₁-C₁₀ alkyl or alkylaryl, and may be the same ordifferent, and X is selected from the group consisting of a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,and c) —SO₂—, in a quantity to ameliorate symptoms of said condition insaid patient; and wherein said condition is selected from the groupconsisting of depression, anxiety, schizophrenia, schizoaffectivedisorder, an eating disorder, and a sleep disorder.
 19. The method ofclaim 18 wherein R1 is selected from the group consisting of —H,—CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂)₄CH₃ and —OH.
 20. The method of claim 18wherein R2 is selected from the group consisting of —H, —CH₃ and CH₂Ph.21. The method of claim 18 wherein X is selected from the groupconsisting of —CH₂—, and —C(CH₃)₂—.
 22. The method of claim 18 whereinsaid compound is an antagonist of 5HT₂ serotonin receptors.
 23. Themethod of claim 18 wherein said compound is an antagonist of both 5HT₂receptors and H1 receptors.
 24. A method of blocking a 5HT₂ receptor ina patient in need thereof, comprising the step of identifying a patientthat would benefit from blocking of the 5HT2 receptor, and administeringto said patient a compound of formula

wherein R1 and R2 are selected from the group consisting of —H, —OH,—OCH₃, halogen, aryl, alkylaryl, and substituted or unsubstitutedbranched or unbranched C₁-C₁₀ alkyl or alkylaryl, and may be the same ordifferent, and X is selected from the group consisting of a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,and c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; and —SO₂—, in a quantity to sufficient to blocksaid 5HT₂ receptor, wherein said method is carried out to treat acondition selected from the group consisting of depression, anxiety,schizophrenia, schizoaffective disorder, an eating disorder, and a sleepdisorder.
 25. A method of blocking an H1 receptor in a patient in needthereof, comprising the step of identifying a patient that would benefitfrom blocking of the H1 receptor, and administering to said patient acompound of formula

wherein R1 and R2 are selected from the group consisting of —H, —OH,—OCH₃, halogen, aryl, alkylaryl, and substituted or unsubstitutedbranched or unbranched C₁-C₁₀ alkyl or alkylaryl, and may be the same ordifferent, and X is selected from the group consisting of a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,and c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; and —SO₂—, in a quantity to sufficient to blocksaid 5HT₂ receptor, wherein said method is carried out to treat acondition selected from the group consisting of depression, anxiety,schizophrenia, schizoaffective disorder, an eating disorder, and a sleepdisorder.
 26. A method of blocking both a 5HT₂ receptor and an H1receptor in a patient in need thereof, comprising the step ofidentifying a patient that would benefit from blocking of the 5HT₂receptor and the H1 receptor, and administering to said patient acompound of formula

wherein R1 and R2 are selected from the group consisting of —H, —OH,—OCH₃, halogen, aryl, alkylaryl, and substituted or unsubstitutedbranched or unbranched C₁-C₁₀alkyl or alkylaryl, and may be the same ordifferent, and X is selected from the group consisting of a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,and c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; and —SO₂—, in a quantity to sufficient to blocksaid 5HT₂ receptor wherein method is carried out to treat a conditionselected from the group consisting of depression, anxiety,schizophrenia, schizoaffective disorder, an eating disorder, and a sleepdisorder.
 27. A compound having the formula

wherein R1 is selected from the group consisting of —OH, —OCH₃, halogen,aryl, alkylaryl, and substituted or unsubstituted branched or unbranchedC₁-C₁₀ alkyl or alkylaryl, and R2 is selected from the group consistingof —H, —OH, —OCH₃, halogen, aryl, alkylaryl, substituted orunsubstituted branched or unbranched C₁-C₁₀ alkyl, substituted orunsubstituted branched or unbranched C₁-C₁₀ alkylaryl and may be thesame or different, and X is selected from the group consisting of a)carbon with two —H substituents, b) carbon with one or two lower alkylsubstituents, and c) a heteroatom or heteroatomic group selected fromthe group consisting of —O—; —S—; and —SO₂—.
 28. The compound of claim27 wherein R1 is selected from the group consisting of —CH₂CH₂CH₂Ph,—OCH₃, —CH₂(CH₂)₄CH₃, phenyl, and —OH.
 29. The compound of claim 27wherein R2 is selected from the group consisting of —H, —CH₃ and CH₂Ph.30. The compound of claim 27 wherein X is selected from the groupconsisting of —CH₂—, —C(CH₃)₂—, —O— and —S—.
 31. A pharmaceuticalcomposition comprising, a compound of formula

wherein R1 is selected from the group consisting of —OH, —OCH₃, halogen,aryl, alkylaryl, and substituted or unsubstituted branched or unbranchedC₁-C₁₀ alkyl or alkylaryl, and R2 is selected from the group consistingof —H, —OH, —OCH₃, halogen, aryl, alkylaryl, substituted orunsubstituted branched or unbranched C₅-C₁₀ alkyl, substituted orunsubstituted branched or unbranched C₁-C₁₀ alkylaryl and may be thesame or different, and X is selected from the group consisting of a)carbon with two —H substituents, b) carbon with one or two lower alkylsubstituents, and c) a heteroatom or heteroatomic group selected fromthe group consisting of —O—; —S—; and —SO₂—; and a pharmaceuticallyacceptable carrier.
 32. The pharmaceutical composition of claim 31wherein R1 is selected from the group consisting of —CH₂CH₂CH₂Ph, —OCH₃,—CH₂(CH₂)₄CH₃ and —OH.
 33. The pharmaceutical composition of claim 31wherein R2 is selected from the group consisting of —H, —CH₃ and CH₂Ph.34. The pharmaceutical composition of claim 31 wherein X is selectedfrom the group consisting of —CH₂—, and —C(CH₃)₂—, —O— and —S—.
 35. Acompound having the formula

wherein R1 is selected from the group consisting of —H, —OH, —OCH₃,halogen, aryl, alkylaryl, and substituted or unsubstituted branched orunbranched C₁-C₁₀ alkyl or alkylaryl, and R2 is selected from the groupconsisting of —OH, —OCH₃, halogen, aryl, alkylaryl, substituted orunsubstituted branched or unbranched C₅-C₁₀ alkyl, substituted orunsubstituted branched or unbranched C₁-C₁₀ alkylaryl and may be thesame or different, and X is selected from the group consisting of a)carbon with two —H substituents, b) carbon with one or two lower alkylsubstituents, and c) a heteroatom or heteroatomic group selected fromthe group consisting of —O—; —S—; and —SO₂—.
 36. The compound of claim35 wherein R1 is selected from the group consisting of —CH₂CH₂CH₂Ph,—OCH₃, —CH₂(CH₂)₄CH₃ phenyl, and —OH.
 37. The compound of claim 35wherein R2 is CH₂Ph.
 38. The compound of claim 35 wherein X is selectedfrom the group consisting of —CH₂—, and —C(CH₃)₂—, —O— and —S—.
 39. Apharmaceutical composition comprising, a compound of formula

wherein R1 is selected from the group consisting of —H, —OH, —OCH₃,halogen, aryl, alkylaryl, and substituted or unsubstituted branched orunbranched C₁-C₁₀ alkyl or alkylaryl, and R2 is selected from the groupconsisting of —H, —OH, —OCH₃, halogen, aryl, alkylaryl, substituted orunsubstituted branched or unbranched C₅-C₁₀ alkyl, substituted orunsubstituted branched or unbranched C₁-C₁₀ alkylaryl and may be thesame or different, and X is selected from the group consisting of a)carbon with two —H substituents, b) carbon with one or two lower alkylsubstituents, and c) a heteroatom or heteroatomic group selected fromthe group consisting of —O—; —S—; and —SO₂—, and a pharmaceuticallyacceptable carrier.
 40. The pharmaceutical composition of claim 39wherein R1 is selected from the group consisting of —CH₂CH₂CH₂Ph, —OCH₃,—CH₂(CH₂)₄CH₃ and —OH.
 41. The pharmaceutical composition of claim 39wherein R2 is CH₂Ph.
 42. The pharmaceutical composition of claim 39wherein X is selected from the group consisting of —CH₂—, and —C(CH₃)₂—,—O— and —S—.
 43. A compound having the formula